Diabetes drug inhibits dangerous inflammation of the adipose tissue
The abdominal fat tissue of obese people is chronically inflamed. This is considered a major cause for the development of diabetes type 2. In normal weight mice a specific group of immune cells holds this inflammation at bay. Scientists of the German Cancer Research Center and Harvard Medical School have now published in Nature that, these immune cells activate a diabetes drug. The activated immune cells not only curb the dangerous inflammation, but also ensure that normal sugar metabolism.
The same applies to humans as to mice: the abdominal fat tissue of severely overweight individuals is chronically inflamed. Inflammation promotes insulin resistance and type 2 diabetes, and is also thought to be one of the factors that increase the risk of cancer in obese people.
The cause of the inflammation are macrophages, which migrate in large numbers into the abdominal fat tissue. There they release messenger substances that further fuel the inflammatory processes. dr Markus Feuerer from the German Cancer Research Center, who until recently worked at Harvard Medical School, made a sensational discovery there: he found a group of specialized immune cells, so-called regulatory T cells, in the abdominal fat tissue of normal-weight mice, which keep the inflammation in check. In the abdominal fat of obese mice, however, this very cell population was almost completely absent. “Using experimental methods, we were able to multiply these anti-inflammatory T cells in obese mice. As a result, the inflammation subsided and the sugar metabolism normalized,” says Feuerer.
In his new work, Markus Feuerer, together with his former colleagues from Diane Mathis' group at Harvard Medical School, discovered the cell nucleus protein PPARγ as the molecular master switch that controls the anti-inflammatory activity of regulatory T cells. The immunologists bred mice whose regulatory T cells cannot produce PPARγ. Hardly any anti-inflammatory T cells were found in the abdominal fat of these animals, but there were significantly more pro-inflammatory macrophages than in normal conspecifics.
PPARγ is well known to medical professionals as the target molecule of a class of diabetes drugs: the glitazones, also known as “insulin sensitizers”, activate this receptor molecule in the cell nucleus. Until now, doctors had assumed that the glitazones mainly improve sugar metabolism by activating PPARγ in the fat cells. Markus Feuerer and colleagues therefore first tested whether the drugs also act directly on the anti-inflammatory immune cells. This appears to be the case, because after glitazone treatment, the number of anti-inflammatory cells in abdominal fat increased in obese mice while the number of pro-inflammatory macrophages decreased.
Does the effect on the anti-inflammatory T cells possibly even contribute to the therapeutic effect of the drugs? The results support this: in obese mice, glitazone treatment improved metabolic parameters such as glucose tolerance and insulin resistance. However, in the genetically modified animals, whose regulatory T cells cannot produce PPARγ, the drug did not normalize the sugar metabolism.
"This is a completely unexpected effect of this well-known group of drugs," says Feuerer. Initial studies indicate that there is also a specific population of regulatory T cells in human abdominal fat. "But we still have to check whether these cells actually reduce the inflammation of the adipose tissue and whether we can also influence them with glitazones," explains the DKFZ immunologist. "Another very important result of our current work is that for the first time we can specifically address a specific population of regulatory T cells with an active substance. This opens up perspectives for the treatment of many diseases.”
Chronic inflammation of adipose tissue is also considered a growth driver for many cancers. Cancer researchers are therefore also interested in the possibility of containing such inflammations with a drug.
Daniela Cipolletta, Markus Feuerer, Amy Li, Nozomu Kamei, Jongsoon Lee, Steven E. Shoelson, Christophe Benoist and Diane Mathis: PPARg is a major driver of the accumulation and phenotype of adipose-tissue Treg cells. Nature 2012, DOI: 10.1038/nature11132
With more than 2.500 employees, the German Cancer Research Center (DKFZ) is the largest biomedical research facility in Germany. More than 1000 scientists at the DKFZ research how cancer develops, record cancer risk factors and search for new strategies to prevent people from developing cancer. They are developing new approaches with which tumors can be diagnosed more precisely and cancer patients can be treated more successfully. Together with the Heidelberg University Hospital, the DKFZ has set up the National Center for Tumor Diseases (NCT) Heidelberg, in which promising approaches from cancer research are transferred to the clinic. The employees of the Cancer Information Service (KID) inform those affected, relatives and interested citizens about the widespread disease cancer. The center is funded 90 percent by the Federal Ministry of Education and Research and 10 percent by the state of Baden-Württemberg and is a member of the Helmholtz Association of German Research Centers.
Source: Heidelberg [DKFZ]
